Cognitive deficits have been recognized as a clinically significant aspect of schizophrenia and the major factor determining successful functional rehabilitation and social reintegration (Green, 1996; Green, 2007). A cognitive impairment in schizophrenia or in other mental disease is an acquired deficit in one or more of memory function, problem solving, orientation and/or abstraction that impinges on an individual's ability to function independently, particularly pronounced in verbal memory, executive functions, attention and vigilance, verbal fluency and motor speed, but also including other functions. Cognitive impairments are not the result of positive or negative symptoms of the disorder or accounted for by motivational deficits (Harvey et al, 2004). In most cases cognitive impairments do not worsen or improve with illness progression (Harvey et al, 2004; Hoff et al, 1999). There are no accepted treatments for cognitive deficits in schizophrenia. Currently available antipsychotic treatments do not improve cognition beyond practice effects (Goldberg et al, 2007; Keefe et al, 2007).
Several lines of evidence suggest that the alpha 7 nicotinic acetylcholine receptor (α7-nAChR) could be involved in cognitive dysfunctions in schizophrenia. A link between P50 sensory gating deficits displayed by schizophrenics and a defect on chromosome 15q14, the site of the α7-nAChR gene (Chini et al., 1994), was established by Freedman et al., 1997. Polymorphisms in the α7-nAChR promoter region that decreased transcription were more prevalent in schizophrenic patients than in the control subjects (Leonard et al., 2002). Postmortem studies have demonstrated that α7-nAChR levels are decreased in brains of schizophrenia patient's (Freedman et al., 1995). α7-nAChRs are expressed in key brain areas important for learning and memory (hippocampus, prefrontal cortex and amygdala). Activation of the α7-nAChR has been shown to modulate glutamatergic, GABAergic and cholinergic neurotransmitter release and to improve cognition in a variety of different pre-clinical animal models.
Novel α7-nAChR activators have been developed for the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors. Although it has been assumed that α7-nAChR activator treatment might improve cognitive deficits controversial data and variation of individual cognitive responses to α7-nAChR activator treatments have so far hindered the development of α7-nAChR activator based treatments of cognitive impairments, e.g. it is not known why some patients do not respond to these medications. Consequently, there is a need to predict in advance of treatment whether a patient suffering from cognitive impairments or dysfunctions is likely to be responsive to treatment with an α7-nAChR activator. Accordingly, ways for predicting responsiveness to an α7-nAChR activator in patients with cognitive impairments or dysfunctions are urgently needed in the art.